Basic and clinical research indicate a close association between ingestive behavior and drug-seeking. This laboratory has shown that sustained negative energy balance augments behavioral and cellular effects of psychostimulants. A key endocrine response to negative energy balance is hypoinsulinemia, evident in both plasma and cerebrospinal fluid (CSF). The objective of this proposal is to determine whether central insulin replacement, as delivered by osmotic minipumps, prevents the augmentation of amphetamine effects in chronically food-restricted rats. The first aim is to determine if the output of the minipump remains stable throughout a 14-day period, and whether addition of an anti-aggregant or protease inhibitor helps to maintain delivery of the intended dose. The second aim is to determine the dose of insulin that restores CSF insulin level of food-restricted rats to the control level, as measured by CSF sampling and radioimmunoassay. The third and fourth aims are to determine if intracerebroventricular insulin replacement during food restriction reverses the augmentation of amphetamine's stimulant and rewarding effects. Stimulant effects are measured using photobeam interruption to count horizontal and vertical movements. Rewarding effects are measured by the degree of threshold-lowering for electrical brain stimulation reward. Results of this research may shed light on the high comorbidity of drug abuse and eating disorders.